tbuckley/cabot-search huggingface dataset:
Injectable alginate hydrogels for synergistic tumor combination therapy through repolarization of tumor-associated macrophages
Authors: Tingting Xiao, Jianzhi Zhu, Liang Jia, Hailong Che, Jie Liu, J. Deckers, Jan C.M. van Hest, Xiangyang Shi
Journal: Journal of Controlled Release (2022)

Locally administered drug delivery systems are promising as they allow to circumvent the side effects associated with systematic administration. In this study, we constructed multifunctional hydrogels by simply mixing commercial alginate (ALG) sols with glucose oxidase (GOx)-conjugated polyacrylic acid-stabilized iron oxide nanoparticles (GPI NPs) and Toll-like receptor 7/8 agonist resiquimod (R848). The injectable sols were able to transform into hydrogels (GPI/R848@ALG) by the ionic cross-linking between ALG and physiological Ca2+ to trap the therapeutic components within the hydrogel framework. Upon intratumoral injection, the hydrogels were employed for starvation therapy, promoted chemodynamic therapy and tumor-associated macrophages (TAMs) repolarization. The energy supply was blocked by consuming the intratumoral glucose via the GOx-catalyzed conversion of glucose into gluconic acid and hydrogen peroxide (H2O2).In vitro results showed that the generated H2O2 could be further converted into highly cytotoxic hydroxyl radicals (·HO) by the Fenton reaction to induce enhanced chemodynamic therapy. The TAMs repolarization studies in vitro exhibited that the GPI/R848@ALG hydrogels up-regulated the expression of CD86 by 63% and down-regulated the proportion of CD206 by 14% with a synergistic effect of the presence of Fe3O4 and R848, suggesting that the multifunctional hydrogels exert functions to direct the remodeling of TAMs from the tumor supportive M2-like phenotype to the tumor destructive M1-like phenotype to further contribute to the antitumor effect. Moreover, both in vitro and in vivo experiments demonstrate that the multifunctional hydrogels exhibit admirable antitumor performance towards 4T1 tumors. This work thereby provides a promising multifunctional nanoplatform for synergistic cancer starvation therapy, chemodynamic therapy and TAMs repolarization.
How we treat NK/T-cell lymphomas
Authors: Eric Tse, Wei-Li Zhao, Jie Xiong, Yok-Lam Kwong
Journal: Journal of Hematology & Oncology (2022)

Abstract Natural killer (NK)/T-cell lymphomas are aggressive malignancies with a predilection for Asian and South American populations. Epstein–Barr virus (EBV) infection in lymphoma cells is universal. Predominantly extranodal, NK/T-cell lymphomas are divided clinically into nasal (involving the nose and upper aerodigestive tract), non-nasal (involving the skin, gastrointestinal tract, testes, and other organs), and aggressive leukaemia/lymphoma (involving the marrow and multiple organs) subtypes. Initial assessment should include imaging with positron emission tomography computed tomography (PET/CT), quantification of plasma EBV DNA as a surrogate marker of lymphoma load, and bone marrow examination with in situ hybridization for EBV-encoded small RNA. Prognostication can be based on presentation parameters (age, stage, lymph node involvement, clinical subtypes, and EBV DNA), which represent patient factors and lymphoma load; and dynamic parameters during treatment (serial plasma EBV DNA and interim/end-of-treatment PET/CT), which reflect response to therapy. Therapeutic goals are to achieve undetectable plasma EBV DNA and normal PET/CT (Deauville score ≤ 3). NK/T-cell lymphomas express the multidrug resistance phenotype, rendering anthracycline-containing regimens ineffective. Stage I/II nasal cases are treated with non-anthracycline asparaginase-based regimens plus sequential/concurrent radiotherapy. Stage III/IV nasal, and non-nasal and aggressive leukaemia/lymphoma cases are treated with asparaginase-containing regimens and consolidated by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable patients. Autologous HSCT does not improve outcome. In relapsed/refractory cases, novel approaches comprise immune checkpoint blockade of PD1/PD-L1, EBV-specific cytotoxic T-cells, monoclonal antibodies, and histone deacetylase inhibitors. Future strategies may include inhibition of signalling pathways and driver mutations, and immunotherapy targeting the lymphoma and its microenvironment.
NFB-01. Central nervous system tumors in Von Hippel-Lindau multisystem disorder: are there preventive approaches to escape tumor initiation at a young age?
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula, Walid Smaoui
Journal: Neuro-Oncology (2022)

Abstract In pediatric neuro-oncology, the likelihood of an underlying tumor predisposition condition should be considered for all types of brain tumors. The aim of this study was to report the dramatic history of a VHL Tunisian family with many affected adolescents presenting central nervous system hemangioblastomas among wich many died in their twenties and those who survived suffered from depression and suicide attempts. To provide optimal clinical care and genetic counseling to affected patients and their young relatives, we conducted a literature review to answer the major question for this family: are there any preventive approaches to escape tumor initiation in our at-risk relatives at young age? The onset of VHL syndrome at the index case of our Tunisian family was at the age of 40 years when she presented a blurred vision on the right, related to retinal angiomatosis. The evolution was caraterised by recurrent eye lesions, the development of multiple renal tumors and hemangioblastomas at the cerebral, cerebellar and cervical spinal cord levels with neurologic symptoms and various functional nervous sequels after neurosurgical resections. Familial features of VHL were present in half of her siblings (6 among 12). Her 2 adolescent sisters, dead at the age of 20, harbored cerebral hemangioblastomas, whereas 2 of her brothers who died respectively at the age of 21 and 47 years harbored respectively ocular angiomas and vertebral angiomas. A third 48 year-old alive brother harbored cerebral hemangioblastoma as well as renal cell carcinoma. Only preimplantation genetic diagnosis (PGD) to select unaffected embryos can be applied to prevent the disease. High-throughput methods such as microarrays and sequencing are available nowadays for late-onset disorders with genetic predispositions. Long term surveillance and timely preventive treatment of lesions are crucial for VHL disease carriers. Effective psychosocial support to vulnerable children and their families is also essential.
An open label, nonrandomized, multisite phase II trial combining bevacizumab, atezolizumab, and rucaparib for the treatment of previously treated recurrent and progressive endometrial cancer.
Authors: William Hampton Bradley, Monica Prasad Hayes, Nicolas Taylor, Janet Sue Rader, Erin Bishop, Elizabeth Hopp, Lindsey Allison McAlarnen, Melodee Liegl, Pippa Simpson, Denise Uyar
Journal: Journal of Clinical Oncology (2022)

5510 Background: Patients with metastatic recurrent endometrial cancer have limited effective therapies. Single agent pembrolizumab is utilized in mismatch repair deficient (MMRd) patients, while the combination of lenvatinib and pembrolizumab is now more commonly used in MMR intact patients who have progressed after chemotherapy combinations. This trial investigated a novel three drug regimen. Methods: Patients with recurrent endometrial cancer not amenable to curative intent surgery or radiation after one or two lines of therapy were eligible regardless of histology. This study is a multicenter, open-label, nonrandomized phase II trial. All subjects initially received the three-drug combination of rucaparib, bevacizumab, and atezolizumab. The primary goal of this trial was to estimate the overall response rate in these patients, and secondarily to estimate the progression-free and overall survival of patients treated with this triplet combination. Total enrollment was 30, with the first six subjects participated in a safety lead-in. Treatments until progression, toxicity, or clinician choice. Subjects could continue past progression if, in the estimate of the treating clinician and subject, clinical benefit was being provided. Subjects were eligible for analysis if they received at least one cycle and had one post-dose tumor assessment. The ORR assumption was 27% with a lower bound of 14%. Results: 30 subjects were enrolled between 07/2019 and 06/2021. Of these 26 were evaluable. Median follow up at cut off was 14.9 months. 23 subjects had clinical benefit, with 1 (4%) with CR, 9 (39%) with PR, and 13 (57%) with stable disease as best response. Overall median event-free (progression or death) was 5.3 (95% CI 2.7-7.9) months and overall survival 13.3 (95% CI NA) months at cut off. Median duration of therapy was 4.4 months (IQR 1.7-7.3), with 4 subjects remaining on study directed therapy at data cut off. Histology distribution was 50% serous, 20% endometrioid, and 13% carcinosarcoma. 19 pts were White, 8 African American, 2 identified as Asian, 1 unknown. In the MMR deficient patients, event-free probability was 11.9 months. Grade 3 or 4 treatment related adverse events occurred in 50% patients. Conclusions: To our knowledge, this trial represents the first use of a non-chemotherapy-based triplet therapy for recurrent endometrial cancer. The combination of rucaparib, bevacizumab, and atezolizumab may safely be used to treat recurrent/persistent endometrial cancer. This combination demonstrates clinically meaningful improvement in response, with acceptable toxicity. Enhanced response to therapy was seen in MMR deficient subjects. Clinical trial information: NCT03694262.
Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia
Authors: Marisa R. Morrow, Battsetseg Batchuluun, Jianhan Wu, Elham Ahmadi, Julie M. Leroux, Pedrum Mohammadi-Shemirani, Eric M. Desjardins, Zhichao Wang, Evangelia E. Tsakiridis, Declan C.T. Lavoie, Amir Reihani, Brennan K. Smith, Jacek M. Kwiecien, James S.V. Lally, Tracy L. Nero, Michael W. Parker, Kjetil Ask, John W. Scott, Lei Jiang, Guillaume Paré, Stephen L. Pinkosky, Gregory R. Steinberg
Journal: Cell Metabolism (2022)
Identification of cardioprotective miRNAs (protectomiRs) in a porcine model of acute myocardial infarction and cardioprotection by ischemic conditioning
Authors: RN Nagy, A Makkos, T Baranyai, Z Giricz, B Kiss, LG Puskas, N Farago, D Lukovic, M Gyongyosi, A Gorbe, P Ferdinandy
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA; NVKP-16-1-2016-0017 National Heart Program and OTKA-FK 134751) MTA-SE System Pharmacology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary Introduction Changes in the expression profile of microRNAs contribute to cardioprotective signaling. We have previously identified cardioprotective microRNAs, termed protectomiRs, by a systematic analysis of microRNA expression pattern in myocardial infarction and cardioprotection induced by ischemic conditioning in rats. ProtectomiRs may be important therapeutics for cardioprotection. Purpose We aimed to identify protectomiRs in a translational porcine model of reperfused acute myocardial infarction (AMI) and cardioprotection, and validate their cardiocytoprotective effect. Methods We used cardiac tissue samples from our previous study in closed-chest AMI model in domestic pigs. Pigs were subjected to sham operation (Sham), ischemia/reperfusion to induce AMI (AMI) or preconditioning (IPreC), postconditioning (IPostC), and remote perconditioning (RIPerC). Tissue samples were collected from the infarcted region of the left ventricles. MiRNA expression pattern was detected by high-throughput qRT-PCR. Potential protectomiRs were selected by systematic comparison of significant expression changes due to different conditioning stimuli vs. AMI. To validate the cardiocytoprotective effect of potential protectomiRs, isolated rat cardiomyocytes were transfected with specific miRNA mimics or inhibitors (antagomiRs) of the selected protectomiRs, and the survival of cells was measured after simulated ischemia/reperfusion injury. Results Expression of 221 miRNAs was assessed. Expression of 57 microRNAs were changed by IPreC, 54 by IPostC and 68 by RIPerC as compared to AMI (min. 1,5×log2 fold-change, -log10p&amp;gt;1,31 vs. AMI). Expression of 14 microRNAs changed significantly due to all three conditionings vs. AMI (10 miRNAs were downregulated and 4 upregulated). Rat homologs of these 14 protectomiR candidates were identified and 13 showed 100% sequence homology with the original pig miRNAs. The selected miRNAs (9 antagomiRs and 4 miRNA mimics) were transfected in isolated rat cardiomyocytes. Modulation of 2 mimics of these miRNAs significantly improved the survival of cells after ischemia/reperfusion injury (due to intellectual property protection, we do not disclose the protectomiRs here). Conclusion Here we identified 2 miRNAs in a clinically relevant porcine model of AMI that can be potential therapeutic protectomiRs.
Clinical impact of DNA methylation status on first-line antiepidermal growth factor receptor treatment in patients with metastatic colorectal cancer.
Authors: Hiroki Osumi, Kota Ouchi, Eiji Shinozaki, Shin Takahashi, Akira Ooki, Keitaro Shimozaki, Izuma Nakayama, Takeru Wakatsuki, Mariko Ogura, Daisuke Takahari, Keisho Chin, Kensei Yamaguchi, Chikashi Ishioka
Journal: Journal of Clinical Oncology (2022)

3528 Background: The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer. However, there is a lack of consensus of CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. Previously, we reported that genome-wide DNAmethylation statuscould predict the effect of epidermal growth factor receptor (EGFR) inhibitors more accurately than previously reported methylation classifications (Ouchi et al. Cancer Sci 2015). Moreover, we had developed a DNA methylation assay based on MethyLight to reflect genome-wide DNA methylation status and reported its usefulness in predicting prognosis in patients with metastatic colorectal cancer (mCRC) treated with EGFR inhibitors as a third-line chemotherapy (Ouchi et al. Cancer Sci 2022). This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with mCRC treated with first-line EGFR inhibitors. Methods: We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment, and analyzed the associations between genome-wide DNA methylation status using a novel comprehensive methylation marker panel and clinical outcomes and evaluated the predictive power and value of the methylation status. Results: Total 169 patients were included in the final analyses. The frequency of highly methylated CRC (HMCC) was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAFV600E mutation (P &lt; 0.001). Patients with HMCC showed worse clinical outcomes than those with low methylated CRC in terms of response rate (P = 0.017), progression-free survival (PFS; P = 0.004), and overall survival (P = 0.019). In the multivariate analysis, peritoneal metastasis (Hazard ratio (HR): 2.24, P = 0.017), methylation status (HR: 3.04, P = 0.037), and BRAFV600E mutations (HR: 5.83, P = 0.0001) were independent factors for shorter PFS. Conclusions: Genome-wide DNA methylation status may be an independent predictor of first-line EGFR inhibitors in patients with mCRC.
Predictive value of HOMAIR indices for severity of left ventricular diastolic dysfunction and NT-proBNP activity
Authors: N Sapojnic, AP Caraush, V Moscalu, DB Sasu, AI Bitca, AS Durnea, MP Caraush
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Academy of Sciences of Moldova Hypertension (HT) and insulin resistance (IR) often coexist and condition LV diastolic function's alteration. Diastolic dysfunction (DD) identifies hypertensives with high cardiovascular risk independent of LV mass and BP level. NT-pro BNP level serve as a diagnostic and prognostic tools in patient with DD. Several studies suggest that DD severity could be interdependent with some biomarkers (HOMAIR, NT-proBNP). Aim To determine if HOMA IR indices could play a predictive role in appreciating severity of LV diastolic dysfunction/ NT-proBNP activity. Methods 101 hypertensive patients (mean age 50.11±0.79 yrs; 48.51% of men, SBP/DBP: 201.31±7.41/106.25±5.54 mmHg, BMI- 29.38±0.22 kg/m2 , HOMA IR - 2.67±0.81) with DD and IR (HOMAIR &amp;gt; 2.5) were enrolled for the study. Ambulatory blood pressure monitoring (ABPM), transthoracic echocardiography (TE), HOMAIR and NT-pro BNP were performed at baseline and after 6, 12- months period of treatment. DD patterns were appreciated according to ASE/EACVI 2016 guideline. NT-proBNP cut-off value was considered &amp;gt; 125 pg/ml (ESC). Correlation analysis was performed using Pearson’s test. The correlation coefficient was considered weak at &amp;lt;0.3, medium-0.3-0.7 and strong &amp;gt; 0.7-1.0. Statistical significance was appreciated at a P-value &amp;lt;0.05 and highly significant at a P-value &amp;lt;0.001. Results The baseline characteristics of bunch are shown in Fig 1. Diastolic dysfunction, HOMA-IR and NT-proBNP levels demonstrated a statistically significant correlation (p&amp;lt; 0.001). A more advanced patterns of diastolic dysfunction demonstrated a particularly strong relationship with higher HOMA-IR and NT-proBNP levels ( Tab. 1). Conclusion In hypertensives with increase in insulin resistance, progression of the left ventricle disorder could develop. The interrelation is in such manner, that the higher is HOMAIR level, the more advanced patterns of diastolic dysfunction and NT-pro BNP activity occure.
Ciltacabtagene Autoleucel, an Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up
Authors: Thomas Martin, Saad Z. Usmani, Jesus G. Berdeja, Mounzer Agha, Adam D. Cohen, Parameswaran Hari, David Avigan, Abhinav Deol, Myo Htut, Alexander Lesokhin, Nikhil C. Munshi, Elizabeth O'Donnell, A. Keith Stewart, Jordan M. Schecter, Jenna D. Goldberg, Carolyn C. Jackson, Tzu-Min Yeh, Arnob Banerjee, Alicia Allred, Enrique Zudaire, William Deraedt, Yunsi Olyslager, Changwei Zhou, Lida Pacaud, Deepu Madduri, Andrzej Jakubowiak, Yi Lin, Sundar Jagannath
Journal: Journal of Clinical Oncology (2022)

CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups.Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee.At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel-related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report.At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.
Response to: Correspondence on 'Novel imaging biomarkers predict outcomes in stage III unresectable non-small cell lung cancer treated with chemoradiation and durvalumab' by Zheng<i>et al</i>
Authors: Vidya Sankar Viswanathan, Mohammadhadi Khorrami, Khalid Jazieh, Pingfu Fu, Nathan Pennell, Anant Madabhushi
Journal: Journal for ImmunoTherapy of Cancer (2022)

Dear Editor, Dr Zheng et al have mentioned several concerns with the methods and approaches in our study.[1][1] First, they have suggested the use of sophisticated and rigorous dimensionality reduction methods for validation. We would like to point out that least absolute shrinkage and selection
MEDB-53. Incidence of Hearing impairment in childhood Medulloblastoma Survivors treated in King Fahad Medical City KFMC Saudi Arabia
Authors: Mohammed Al Mahmodi, Nahla Ali Mobark, Demah A Almowanes, Haya N AlGhunaim, Nad E Kattan, Wael abdel Rahman Aljabarat, Fahad Alotabi, Mohammed Rayis, Zaid G AlNaqib, Ali Abdullah O Balbaid, Musa Alharbi
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma MB is the most common childhood CNS tumor treated with intensive multimodalities therapy Surgery, Radiation and Cisplatin chemotherapy which causing significant Hearing impairment (HI) with profound impact on child’s quality of life. METHOD: Retrospective study evaluating risk factors &amp; (HI) incidence in childhood MB survivors treated in KFMC between 2010 and 2020. (HI) was graded using the National Cancer Institute (NCI) Grades (1-4) ALL patients received 6 weeks of Risk adapted CSI radiotherapy concurrent with daily oral Etoposide. patients were treated with 2 different Maintenance chemotherapy German HIT-MED MB protocol 8 Maintenance cycles (Cisplatin 70 mg/m² x 1d /lomustine/VCR) Cumulative dose of Cisplatin 560 mg/m2 KFMC MB SAPHOS protocol 6 Maintenance cycle alternating A&amp;B. cycle A: Cisplatin 90 mg/m² x 1d &amp; 3 weeks of daily oral Etoposide. cycle B: Cyclophosphamide x 2 d &amp; Vincristine Cumulative dose of Cisplatin 270 mg/m2. RESULTS: At Median follow-up of 5 years total of 78 MB survivors, male predominance 66.7% Median age at diagnosis 82 months post end of therapy 28.2% maintain normal hearing while 71.8% had hearing decline compared with baseline audiology Median time of onset of hearing decline was 7 months after start of radiation therapy Significant (HI) (NCI grade 3/4) in 26.9% of patients, and 23.1% required hearing aid use NO statistically difference in incidence of significant (HI) in patients treated with HIT-MED protocol (26.7%) &amp; patients treated with KFMC MB-SAPHOS protocol (27.1%) OR those treated as Average-Risk CSI radiotherapy 22.9% Vs High-Risk CSI radiotherapy (30.2%), patients age at diagnosis (&amp;lt; or &amp;gt; 5 years) does not affects HI incidence. CONCLUSIONS: significant hearing impairment incidence was not affected by Radiation doses OR cumulative Cisplatin dose. Our study will form base line for future studies to modify therapy related Toxicity and improve outcome of childhood MB in Saudi Arabia.